Microglial Neuroinflammation in Alzheimer’s Disease: Mechanisms and Therapies

Alzheimer’s disease is a progressive neurodegenerative disorder marked by cognitive deterioration, synaptic dysfunction, and neuronal loss. While amyloid-β plaques and neurofibrillary tangles have traditionally dominated the pathological paradigm, emerging evidence underscores the pivotal role of microglial-mediated neuroinflammation in disease initiation and progression. Microglia, the central nervous system’s resident immune cells, dynamically shift from a homeostatic to a reactive state in response to pathological cues, contributing to chronic inflammation, impaired clearance of pathological aggregates, and neurotoxicity. This review comprehensively examines the dualistic nature of microglial responses across Alzheimer’s disease pathogenesis, highlighting recent insights into their molecular signaling pathways, including TREM2, CD33, NLRP3 inflammasome, and APOE. We further explore the regulatory influence of the gut–brain axis and immunometabolic dysfunction on microglial behavior. Finally, we discuss current and emerging therapeutic strategies, ranging from natural compounds and synthetic modulators to immunotherapy and microbiota-targeted interventions, that aim to restore microglial homeostasis. By integrating mechanistic, translational, and therapeutic perspectives, this review advocates for a paradigm shift toward immunomodulatory approaches targeting microglia as promising disease-modifying strategies in Alzheimer’s disease.